Some epidemiological aspects of liver cirrhosis and hepatocellular carcinoma in Sweden

Background: Contemporary epidemiological studies examining incidence rates (IR) of cirrhosis and hepatocellular carcinoma (HCC) in Swedish populations are scarce. Cirrhosis and HCC are associated with a significant burden of health inequity and stigma. The importance of socioeconomic status (SES) in cirrhosis survival has scarcely been studied in Sweden. The impact of SES on HCC incidence and prognosis had never been investigated in Sweden. Aim: The overall aim of this thesis was to describe the contemporary epidemiology of cirrhosis and HCC in Swedish settings. We also aimed to improve the understanding of the importance of sociodemographic and clinical characteristics for the clinical course and early identification of cirrhosis and HCC. Methods: We used population-based medical registries to identify adult patients diagnosed with cirrhosis in the region of Halland between 2011 and 2018. Annual crude IR of cirrhosis were calculated (Paper I). Patients were followed-up until date of liver transplantation, death, moving from Halland, or until December 31st, 2019; whichever occurred first. Cox regression models were employed to estimate unadjusted and adjusted hazard ratios (HR and aHR) for several clinical and sociodemograhic variables (Paper II). The nationwide quality register for liver cancer was used to identify all adult patients diagnosed with HCC in Sweden between 2012 and 2018. Poisson regression was used to estimate IRs of HCC across several populations of interest (Paper III). Data extracted from the quality register were cross-linked to data from other nationwide registers. Multivariable logistic regression models were employed to identify factors associated with an increased likelihood for having unrecognized cirrhosis, or late-stage HCC at diagnosis. Patients were followed-up until the date of death, emigration from Sweden, or until December 31st, 2020; whichever occurred first. Cox regression modelling was used for the estimation of HRs and aHRs for several clinical variables (Paper IV). IRs of HCC were estimated for the whole adult population of Sweden and stratified by HCC etiologies (Paper V). Patients were stratified into those with non-alcoholic fatty liver disease (NAFLD) associated HCC and those with non-NAFLD-HCC. Furthermore, those with NAFLD-HCC were divided into those with and without underlying cirrhosis. Results: We identified a total of 598 patients with cirrhosis. The IR of cirrhosis in adults in Halland was estimated at 30 per 100,000 person-years, 39 for men, and 22 for women (Paper I). Patients with a low SES, defined as a low occupational skill level, had more advanced cirrhosis at diagnosis, lower mean survival, and higher mortality risk when compared to patients with high SES (Paper II). A total of 3,473 adult patients with HCC were identified and 68% were diagnosed with a late-stage HCC. Sex, country of birth, and individual- and contextual level SES were associated with the IRs of HCC. Men with a low household income and/or living in the most deprived neighborhoods had the highest IR of HCC (Paper III). Among patients with HCC, 2670 (77%) had underlying cirrhosis. Cirrhosis was unrecognized in 39% of all patients with underlying cirrhosis. Unrecognized cirrhosis was associated with more advanced HCC at diagnosis and worse survival (Paper IV). Among the 3,473 patients with HCC, 21% had underlying NAFLD, which also was the second-leading cause of HCC and the fastest- increasing cause of HCC (Paper V). Conclusions: The IRs of cirrhosis may be higher than previously estimated. Low SES was associated with a worse prognosis in cirrhosis, higher IRs of HCC, and increased risk of unrecognized cirrhosis in HCC. NAFLD is an increasing cause of cirrhosis and has become a leading cause of HCC. NAFLD is also associated with an increased risk of cirrhosis unrecognition in HCC

Antiepileptic drug utilization : need of sex-specific information and decision support

Antiepileptic drugs are used for the treatment of epilepsy and for other neurological and psychiatric conditions, and therefore is prescribing of antiepileptic drugs a concern for physicians from many disciplines. The age and sex-specific prevalence, as well as the role of sex and gender aspects, vary between the conditions for which antiepileptic drugs are used. The overall aim of this thesis was to gain more understanding of the use of antiepileptic drugs on various diagnoses, focusing on sex/gender differences, and to explore physicians' perceptions of sex and gender in decision making on drug treatment. The first two studies describe the antiepileptic drugs used in epilepsy and other conditions. Clear age and gender differences in the use of specific anti-epileptics were observed. The use of antiepileptic drugs in children and adolescents was mainly limited to epilepsy and the individual antiepileptic drugs prescribed appeared to be in accordance with approved indications and treatment guidelines. However, some antiepileptic drugs were used off-label in children and adolescents. The third study evaluated the effect of a warning issued by the European Medicines Agency in November 2014 on restricted prescribing of valproic acid to girls and women of childbearing potential. The analyzes showed that the warning only affected the prescribing in girls and women with a psychiatric diagnosis. Prescribing to girls and women with epilepsy had decreased long before the warning was issued, which could indicate an increased awareness of the teratogenic risk of valproic acid among neurologists treating women with epilepsy. The fourth study examined how primary care physicians perceive sex/gender and gender equality related to drug prescribing. The results showed that physicians experienced insufficient knowledge of sex/gender differences in drug treatment, although their expressed clinical experience indicated some awareness. The patient's sex was considered during diagnosing while drug prescribing decisions followed the regional recommendation lists because these were believed to be evidence-based and gender-neutral. Overall, physicians wanted more education and knowledge about sex and gender in drug treatment. However, finding reliable information about sex and gender aspects for individual drugs may be difficult. This can be facilitated by the web-based knowledge base Janusmed Sex and Gender, as described in the fifth study. In summary, this thesis demonstrates sex differences in use of certain antiepileptic drugs, which probably reflect the different benefit and risk from these between men and women. Knowledge of how antiepileptic drugs are prescribed and used in women and men with different diagnoses may be useful in discussions on rational drug prescribing and to propose measures to improve prescribing behavior. As shown in this thesis, regulatory measures may be one approach to improve rational prescribing and to highlight the importance of the patient's sex. Another approach may be to get acquainted with sex and gender-related pharmacological information through the knowledge base Janusmed Sex and Gender

Dietary Supplement Labeling: Cognitive Biases, Market Manipulation & Consumer Choice

There exists increasing concern that the Dietary Supplements Health and Education Act (DSHEA) has proven ineffective. Much of the concern regards the disparity in legislative treatment between dietary supplements, foods, and pharmaceutical drugs. Namely, while pharmaceutical drugs must undergo years of costly pre-market testing, most supplements, like foods, can immediately enter the market, and only after repeated instances of adverse reactions can the Food and Drug Administration (FDA) remove them. Such a framework appears to belie both consumer expectations and marketing strategies, as supplements tend to be most perceived for their apparent medicinal qualities. This philosophy of waiting for a foreseeable harm also strikes many as unnecessary, inefficient, and immoral. On the other hand, most supplements have proven safe and either benign or reasonably effective. Moreover, before policy-makers mandate extensive pre-market testing of all supplements, consider the likely effect on production: a certain percentage of supplement makers will find the economics of production too costly and will thus leave the market. Granted, foreign markets for supplements might still provide the requisite incentives for production, but a more costly entrance fee into the U.S. market would clearly deter some level of production and convince a number of makers to leave the market altogether. Equally troubling, companies which choose to remain in the market would presumably pass on a portion of the increased costs to consumers, who often bear the costs of heightened regulation. Consequently, many beneficial supplements would be priced out of the reach of consumers who either have become users of those products or could become users. The issue then is one of nuance. Rather than sweeping regulatory intervention, perhaps more carefully-tailored alterations would prove most desirable. This philosophy appears desirable given informational deficiencies among dietary supplement consumers, particularly those with exploitable cognitive biases. Promisingly, such deficiencies may be ameliorated through low-cost measures that promote enhanced communication of product characteristics. For these reasons, this Article proposes a refined approach to dietary supplement labeling that would legally distinguish them on the basis of potential risk and anticipated benefit. Indeed, the existing legal construct of the phrase dietary supplements is both curious and overly simplistic. It includes minerals, vitamins, herbs, botanical extracts, and amino acids - items that are not only functionally different, but which present radically different risks and benefits. Along those lines, the very consumers of supplements should be more carefully distinguished. How might such a revised communicatory model work without precipitating material price increases or deterring beneficial production? One method would entail more carefully-contemplated labeling requirements. Such requirements should enhance consumer risk-assessment and reward reputable supplement manufacturers. To accomplish these goals, labels should reveal potential interactions with pharmaceutical drugs and other supplements, warnings of over-usage, predictable distinctions between health claims and structure/function claims, and a recommended intake range based on age and gender, among other personal characteristics. Of similar benefit would be assured ingredient content, as well as greater coordination between the FDA and the Federal Trade Commission (FTC) in regulating false or misleading supplement claims. Importantly, because such labeling requirements would impose only minimal cost increases to manufacturers

Handover evaluation of UMTS-WiMAX networks

Recently, data traffic movement through a wireless channel is assisted by suggesting and implementing many mechanisms, to achieve the speedy increasing importunity and popularity of the wireless networks. Various wireless technologies can be copulated to develop a heterogeneous network, which is a candidate towards (4G) networks. OPNET modeler (14.5) is used to design simulation modules of the heterogeneous network. During device connection between the worldwide interoperability for microwave access (WiMAX) and universal mobile telecommunication system (UMTS) networks, Performance metrics such as; Jitter end-to-end delay (E-2-E) Throughput is used. The results of the simulation are measured to determine the efficiency of the transfer using WiMAX-UMTS according to the selected metrics. The WiMAX-UMTS has shown valuable improvement in Process Durability, reduction of E-2-E delay, and Jitter. The maximum amount of data transfer and the least amount of delay and Jitter is at 250 sec. Because of the handover operations and data transfer momentum, the worst-case passes in the network when 618 sec is the minimum amount. The efficiency of throughput for WiMAX equal to 0.092666% as for the efficiency of throughput for UMTS equal to 4.633333*10-6 % whereas the E-2-E efficiency a delay equal to 0.5466%

Early life origins of asthma : genetic and environmental factors in twin and kin

During the last decades there has been an upsurge of studies investigating how early life exposures may affect subsequent health outcomes in childhood. For instance, low birth weight and exposure to antibiotics during fetal or early life have been suggested to increase the risk of childhood asthma. Twin- and sibling comparisons can help to account for confounding factors shared within families and to shed light on potential causal pathways. Thus, in Study I, we aimed to investigate if low birth weight, as a proxy for fetal growth restriction in twins, was associated with the development of asthma in a cohort of 10 918 Swedish twins aged 9 or 12 years. We found a significant association which was thought to be explained by unique individual factors and not due to familial confounding or gestational age. It can be speculated that restricted fetal growth affects lung development in utero which influences the risk of developing asthma in childhood. In Study II, we aimed to further understand the adverse effects of restricted fetal growth, by specifically investigating its association with childhood lung function in a cohort of 576 twins aged 9-14 years at invitation to the study. We found a significant association between fetal growth restriction and reduced forced expiratory volume in the first second, which could be explained by unique factors of each twin. Similar effects were found in non-asthmatic individuals, whereas other factors may be of importance for the association between fetal growth and lung function in individuals with asthma. To be able to study asthma in register-based studies, a valid measure of the disease is needed. In Study III, medical records for roughly 1700 individuals, corresponding to prescription dates of asthma medications or to discharge dates accompanying asthma diagnoses and identified from population-based drug- and patient registers, were collected from health care units and evaluated against pre-defined criteria of asthma. We found a high positive predictive value for asthma medication as a proxy for asthma in older children and the majority of children with an asthma diagnosis in the patient register fulfilled pre-defined criteria of asthma. In Study IV, the previously suggested association between antibiotic exposure in fetal and early life and childhood asthma (based on the validated outcome measure from Study III) was investigated in a cohort of 493 785 children. We found an association between antibiotic exposure both in fetal and early life and asthma. Yet, sibling control analyses suggested that the associations were due to shared factors within families, and confounding by indication or reverse causation due to respiratory infections. In conclusion, shared genetic and environmental factors contributed to the association between antibiotics and asthma, but not between fetal growth and asthma and lung function, respectively. Genetically informed designs to control for familial confounding are useful tools to help provide a clearer understanding of the etiology of asthma. In addition, asthma identified from population-based registers can be used as a validated outcome measure and contribute towards future studies on asthma using register-based data

Stroke Epidemiology and Outcome in Southern Sweden

Background: Stroke is a common cause of mortality and disability worldwide and continuously updated, thorough information of itsoccurrence and outcome is needed. In recent years, multiple advances have been made in stroke prevention and treatment that mayhave changed the epidemiology and outcome of stroke.Aims: To investigate updated population-based stroke epidemiology as well as long-term survival, recurrence and functional outcomein southern Sweden.Methods: Paper I: A population-based cohort of 413 consecutive patients with first-ever stroke in 2015-2016 was assembled usingthe prospective hospital-based stroke studies Lund Stroke Register (LSR) and Riksstroke, as well as retrospective searches ofprimary care, outpatient clinic and autopsy sources. Age- and sex-standardized incidence rates were calculated and compared with aprior study from the same study area in 2001-2002.Paper II: A subset of the population-based cohort of 400 patients (only ischemic stroke and intracerebral hemorrhage) was comparedwith LSR and Riksstroke regarding case ascertainment and which patients were not included in the hospital-based stroke studies.Paper III: The 400 individuals in the population-based cohort were followed up after 3 years regarding survival and causes of deathby using the Swedish Causes of Death Register, and stroke recurrence by using medical record review. Index and recurrent strokeswere classified by pathogenetic mechanism using the TOAST classification. Stroke survival at 3 years was compared with priorstudies in our area from 1983-1985, 1993-1995, and 2001-2002.Paper IV: The population-based cohort was followed-up in-person or via telephone at 3-4 years regarding functional outcome (mRS),dependency in activities of daily living (ADL), and health-related quality of life (HRQoL). Data were also collected on potentiallycorrelated health problems after stroke such as fatigue, cognitive impairment and depression.Results: Paper I: The total population-based age- and sex-standardized rate of stroke incidence was 165 per 100 000 person yearsin our study area, a 33% decrease compared with a population-based study in our area from 2001-2002. However, stroke incidencerates did not change for hemorrhagic stroke or among those <65 years.Paper II: LSR detected 363 (91%) of cases while Riksstroke detected 328 (82%). Patients undetected by the hospital-based studieshad high case fatality (44% vs 9%; p=0.001), and those only detected in primary care (n=11) often lived in nursing homes (57%).Those not detected by Riksstroke had less severe stroke (median NIHSS 3 vs 5; p=0.013).Paper III: In total, 265 (66%) survived 3 years after first-ever stroke. Among individuals with ischemic stroke, cardio-aortic embolismas pathogenetic mechanism was associated with the lowest 3-year survival (51/91; 56%). Cardiovascular disease was the cause ofdeath in 59% of cases (79/135). Meanwhile, 8% (32/400) had a recurrent stroke within 3 years, and the pathogenetic mechanism ofischemic stroke changed between first-ever stroke and recurrence in 16/29 (55%) cases. Three-year survival improved between the1980s and the present study (56% vs 66%; p=0.002), but survival did not change significantly between the early 2000s and thepresent study (64% vs 66%; p=0.48. Paper IV: In all, 202 individuals were clinically followed-up after a median of 3.2 years, while 47(12%) stroke survivors were lost to follow-up. Among followed-up survivors, 147 (73%) had favorable functional outcome (mRS≤2)and 134 (69%) reported good-excellent HRQoL. Age, stroke severity, professional care pre-stroke and recurrent stroke (all p<0.001)were predictors of poor functional outcome. Among follow-up variables, fatigue (p=0.001), and stroke severity (p<0.001) wereassociated with dependency in ADL, and fatigue (p<0.001) was also associated with worse HRQoL.Conclusions: Stroke incidence and survival have improved over recent decades, however some subgroups of stroke have notimproved in the same manner. Thorough population-based epidemiological studies of stroke are important to avoid and to possibleselection bias in hospital-based stroke studies. Around 3 of 10 long-term stroke survivors have poor outcome, and fatigue may be asignificant contributor to post-stroke function and health